3-Chloro-tetrahydro-1,3-oxazines or oxazolidines

ABSTRACT

There is provided, novel 3-chlorotetrahydro-1,3-oxazine or oxazolidine compounds, exhibiting antibacterial activity and being of low chlorine potential of the formula:   WHEREIN EACH OF R1 and R2, which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred); wherein each of R5 and R6, which may be the same or different, represent a hydrogen atom or an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred); wherein l represents an integer of 1 or 2 and wherein each of R3 and R4, which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred), a -(CH2)nX group, wherein n represents an integer of from 1 to 20 and wherein X represents a dimethylamino group, a diethylamino group, a trimethylammonium group, a triethylammonium group, a dimethylammonium group, a diethylammonium group, a -COOR7 group, a -OOCR8 group, and a -OR9 group, wherein each of R7 through R9, respectively, represent an alkyl group of from 1 to 5 carbon atoms or a benzyl group. In addition, R3 and R4 can also represent a   group, wherein Y represents a -(CH2)n-W-(CH2)m- group or a &gt;CH-Z group, wherein W represents a -O- atom, a -CH2- group, a &gt;NCH3group, a &gt;NHCH3 group, a &gt;NC2H5 group, a &gt;NHC2H5 group, a &gt;N(CH3)2 group, or a &gt;N(C2H5)2 group, wherein n is the same or different from m and wherein each of n and m represent an integer of from 0 to 2; and wherein Z is defined in accordance with X above.

United States Patent 1 Bodor et al.

[ 3-CHLORO-TETRAHYDRO-1,3-OXAZINES 0R OXAZOLIDINES [75] Inventors:Nicolae S. Bodor; James J.

Kaminski, both of Lawrence, Kans.

[73] Assignee: lnterx Research Corporation,

Lawrence, Kans.

[22] Filed: Apr. 1, 1974 [21] Appl. No; 456,744

[52] U.S. CL. 260/244 R; 260/307 FA; 260/293.66; 424/248; 424/267;424/272 [51] Int. Cl. C07D 265/06 Primary ExaminerSherman D. WintersAttorney, Agent, or Firm Charles N. Blitzer [57] ABSTRACT There isprovided, novel 3-chlorotetrahydro-1,3- oxazine or oxazolidinecompounds, exhibiting antibacterial activity and being of low chlorinepotential of the formula:

(C R Rgl R x- 3 R N R [451 July 29,1975

wherein each of R, and R which may be the same or different, representan alkyl group of from 1 to 20 carbon atoms (C -C being preferred);wherein each of R and R which may be the same or different, represent ahydrogen atom or an alkyl group of from 1 to 20 carbon atoms (C -C beingpreferred); wherein 1 represents an integer of 1 or 2 and wherein eachof R and R which may be the same or different, represent an alkyl groupof from '1 to 20 carbon atoms (C -C being preferred), a (CH ),,X group,wherein n represents an integer of from 1 to 20 and wherein X representsa dimethylamino group, a diethylarnino group, a trimethylammonium group,a triethylammonium group, a dimethylammonium group, a diethylammoniumgroup, a COOR group, a OOCR group, and a OR group, wherein each of Rthrough R respectively, represent an alkyl group of from 1 to 5 carbonatoms or a benzyl group. in addition, R and R, can also represent agroup, wherein Y represents a (Cl-l ),,-W--(CH group or a Cl-l-Z group,wherein W repre- 11 Claims, No Drawings BACKGROUND OF THE INVENTIONwherein each of R and R which may be the same or different, represent analkyl group of from 1 to 20 carbon atoms (C -C being preferred); whereineach of R and R which may be the same or different, represent a hydrogenatom or an alkyl group of from 1 to 20 car:

1. Field of the Invention 5 y H The present invention is directed tonovel antibacteatoms 1- 5 being P wherein f rial low chlorine potentialcompounds and more specif- SefltS an integer 0f 1 9 2 and wherein each f3 n ically, the present invention is directed to a totally new 4 which ybe the same of diffel'fim, p s t n class of such compounds, termed3-chloro-tetrahydr0- y group of from 1 to 20 Carbon atoms is g,1,3-oxazines or oxazolidines as described hereinafter. 10 Preferred), a2)n group, wherein represents 2 Description f the P i Art an integer offrom 1 to 20 and wherein .X represents a it is known in the art thatcertain N-chloro-2- dimethylamiho groupf a diethylamiho group, atl'hhfith- I oxazolidinones possess antibacterial activity. However,ylammohium group, a hieihylammohium g p a review of the literatureconcerning such compounds dimethylammchium p a diethylammohium p, willreadily reveal that these compounds are higher a 1g P a O s group, 9 grup, chlorine potential compounds and as aresult thereof, Whefeifl eachof 1 h g 9 respectively, p e t while such compounds can exhibit asufficient antibacan alkyl group of from 1 to 5 carbon atoms or abenzylterial activity, their higher chlorine potential imparts to group.In addition, R and R, can also represent a these compounds, a bleachcapability. That is, due to their high chlorine potential, the-N-chloro-2- v oxazolidinones, while capable of controlling bacterialgrowth, will also tend to be more corrosive. Conse- 2 y quently, for themost part, these compounds have been 2 employed as bleaching agents.See, US. Pat. No. 3,59l ,bOl

SUMMARY OF THE INVENTION group, wherein Y represents a -(CH ),,W(CH 1group or a CH-.-Z group, wherein W representsv 7 In view of theforegoing, it IS readily apparent that an atom a group, there is a greatneed to develop suitable antibacterial a NHCH3+ group, a NC2H5 groupagents of low chlorine potential, which exhibit suffigroup a N(CH3)2+group or a N(2H5)2+ group: cient antibacterial activity and yet, areless corrosive. wherein n is the Same or dierent from m whereinTherefore, h is one Object of the l invention to each ofn and mrepresent an integer of from O to 2; and develop antibacterial agents oflow chlorine potential, wherein Z is defined in accordance with X abovewhich exhibit sufficient antibacterial activity In the Case where R5 andR6 may represent an alkyl it IS a second ob ect of the present inyentiontodegroup of from 1 to 20 Carbon atoms or a hydrogen velop antibacterialagents which in addition to exhlbltatom, the hydrogen atom form ispreferred. This is true ing sufficient antibacterial activity and ofbeing of low even when R5 and R6 represent a carbon atom range ofchlorine potential, also fail to be relatively corrosive. from 1 to 5.

Finally, it is a third object of the present invention to Where feasibleapplicants prefer to use the p develop antibacterial agents which meetthe above cri- 40 salt (HX Salt) wherein X represents a pharmaceutia areP a F That i cOmPOundS Cally acceptable anion derived from apharmaceutically I Wl'llCi'l, in aqueous media, exhibit sufficientantibacteacceptable acid addition Salt of the Compound though rialactivity over a short time span. afterwhich, decomuse of the free baseis quite acceptable. protofi Posmon i [he cqmpound i 5 salts can easilybe prepared by simply reacting the free Accmdmgly with the foregoing mthe present base compound with a pharmaceuticall acce table invention isdirected to a novel class of low chlorine poacid such as hydrochloricacid hydrogmi'nicpacid tential compounds, which exhibit antibacterialactivity meflmnesulfonic acid and the and are demed nonlpersistam whichCompounds have At this point, it shciuld be emphasized that the term thefollowing formula anti-bacterial as employed in this application alsoincludes anti-fungal activity as well. R1 h'fig R3 The compounds of thepresent invention are readily j prepared by the synthesis procedureoutlined below, R2 i wherein 1 2, 3, 4, R R and l are defined as C]above.

Step l )1 R R I 3 4 +1 0 X H2 (CR R OH R2 4 Step (2):

Y XX

The above reaction scheme is carried out under standard temperature andpressure. With respect to step (1), the solvent employed is one which iscapable of removing water from the first reaction step as it is formed.Without limitation, illustrative solvents capable of achieving thisfunction are benzene, toluene, or xylene. As an alternative embodiment,a desiccant, such as magnesium sulfate or a molecular sieve can beemployed to remove water formed during the reaction.

As for step (2), any conventional chlorinating agent N, 11.00. can beemployed and illustrative of such agents, suit- Next, the final compound(3-chloro-2,2,4,4- able for applicants purpose is NaOCL, Ca(OCl)ttetramethyl-l,3-oxazolidine) was prepared from the BuOCl,N-chlorosuccinimide and chlorine. Naturally, precursor material. To 175ml of 0.65 M sodium hypothe aforementioned chlorinating agents are onlyilluschlorite (0.11 mole) at 0C, there was added dropwise trative of thewide variety of conventional chlorinating with stirring, the precursorcompound obtained earlier, agents suitable for applicants purpose and itis believed while the reaction mixture was maintained between a thatthis is understood by the skilled artisan concerned pH of from 4 to 6through the use of 1M HCl. with the subject matter of this invention.After 30 minutes at 0C, the reaction mixture was ex- A betterunderstanding of the present invention will tracted with dichloromethaneand the extracts were be gained from a review of the following examples,combined and dried over anhydrous sodium sulfate. which are simplyillustrative and non-limitative thereof. Following filtration, thedichloromethane was removed under reduced pressure and the 3-chloro-2,2,4,4-

EXAMPLE 1 tetramethyl-l ,3-oxazolidine was isolated as a pale yel-(Preparation of low liquid, bp 65-67C (12 mm), 10.1 g (0.062 mole),3-chloro-2,2,4,4-tetramethy1-1,3-oxazo1idine) a 56% yield.

Firstly, the precursor compound (2,2,4,4-tetrameth- Analysis Calculatedfor: 1 14 C, 5137; 1 yl-l,3-oxazolidine was prepared. To 237 g. (3.0mole) 8-62; and Found: C, 51-36311, 8-77; of2-amino-2-methyl-1-propanol, there was added apand proximately 750 ml ofdry benzene containing 174 g Once the final compound was prepared, itwas sub- (3.0 mole) of acetone. 4 jected to antibacterial and stabilitystudies as described A few crystals of para-toluenesulfonic acid were inTables 1 and 2, set forth on the following pages.

TABLE 1 CONCENTRATION DATA Conditions Positive Germicidal Activity Time(min) Compound 1-1 Diluent Compound c1 12228 10536 10031 9027 6538 46170.1MNaOAc 1-1,o 8.26 10-M 289 m 0.5 0.5 0.5 0.5 0.5 0.5 CHQ O CHE pH 4.61355 ppm c1 1 N CH, 0.1M NaOAc Serum 8.26 X 10-"M 289 ppm 10 3 10 4 10 61 pH 4.6 1355 ppm O.1MNaH.PO, 11.0 8.92 10-M 312 m 1 0.5 0.5 1 3 1 c11,o Z1-1 pH 7.00 z 1463 ppm pp C11 N 11;. 0.1M Natl- P0, Serum 8.92 10-='M312 ppm 0 3 5 7 10 10 a pH 7.00 1463 ppm 0.1M M12840, 11,0 8.13 IO-M 285ppm 5 2 4 2 5 3 CH O CH pH 8.8 1333 ppm CH3 N CH;I 0.1M N212B,O7 Serum8.13 X 10"M 285 ppm 10 4 9 4 10 8 1 pH 8.8 1333 m c1 TABLE 2 STABlLlTYANALYSIS OF 3-CHLORO-2,2,4,4-TETRAMETHYL-l,3-OXAZOLlDlNE EXAMPLE 11(Preparation of 3-chloro-2,2-[spiro-l '-methyl-4 '-piperidinyl ]-4,4-dimethyl-1,3-oxazolidine and its HX salts) Firstly, the precursorcompound, 2,2-[spirol -methyl-4'-piperidinyl]-4,4-dimethyll,3-oxazolidine was prepared. To 44.5 g (0.5 mole) of2-amino-2-methyl-lpropanol, there was added approximately 400 ml of drybenzene containing 56.5 g (0.5 mole) of 1-methyl-4 piperidone. Thesolution was stirred under and Dean- Stark water separator at refluxtemperature.

When the theoretical amount of water was collected, the benzene wasremoved under reduced pressure to yield a brown oil. The precursorcompound was collected as a clear, colorless distillate, bp 6365C (1.2mm), 58.9 g (0.32 mole), 64% yield.

Next, the final compound 3-chloro-2,2-[spiro-lmethyl-4'-piperidinyl]-4,4-dimethyl-1,3-oxazolidine was prepared fromthe precursor material in the manner described. To 50 ml of 0.65 Msodium hypochlorite (0.03 mole) at 0C, there was added with stirring5.52 g (0.03 mole) of the precursor compound obtained earlier.

After 30 minutes at 0C, the pale yellow solid was isolated byfiltration, washed thoroughly with cold water and then dried in vacuoover calcium sulfate to give 3- chloro-2,2-[spiro-l'-methyl-4-piperidinyl]- 4,4-dimethyl-l,3-oxazolidine, mp 4648C,sublimation at 35C (0.5 mm); UV (H 0) )1 max 265 nm, e=270 M' cm.

Analysis Calculated for: C H ClN Oz C, 54.91; H, 8.76; N, 12.81; and CI,16.2. Found: C, 54.77; H, 8.90; N, 12.85; and Cl, 15.].

The methanesulfonate salt of the above-isolated 7 compound was preparedby simply reacting the free base with an ethereal solution ofmethanesulfonic acid, mp l24-125C (dec).

Analysis Calculated for: C H ClN O S: C, 41.96; H, 7.36; N, 8.90; andCl, 11.3. Found: C, 41.27; H, 7.41; N, 8.49; and Cl, 10.6.

In similar fashion, the hydrochloride salt of the aboveisolated compoundwas prepared as follows. To an ethereal solution containing 1.1 g (0.005mole), at 0C, there was added dropwise with stirring, 2 ml of 2.26 MHCl/Et 0, diluted to approximately 25 ml using.

anhydrous ether, (0.0045 mole). The suspension was maintained at 0C for30 minutes and the white solid which formed was isolated by filtrationand thoroughly washed with anhydrous ether under an atmosphere ofnitrogen. The solid isolated was dried in vacuo over calcium sulfate togive the corresponding hydrochloride salt, mp l20l2lC (dec.), 1.18 g(0.0046 mole), 93% yield.

Analysis Calculated for: C H CI N O: C, 47.06; H, 7.90; N, 10.98; andCI, 13.9. Found: C, 44.39; H, 7.56; N, 9.91; and Cl, 13.1.

TABLE 3 Conditions Concentration Data Antibacterial Activity. Time(min.)

Buffer/ Positive Compound pH Diluent Compound C] 12228 10536 10031 90256538 4617 6501 0.1 M NaOAc H O 6.52 X l0 M 231 ppm 1 0.5 0.5 0.5 5 0.5 NH 4.6 1428 CH w ,.c1-1 p ppm CH3 0.1 MNaOAc Serum 5.69 X 10"M 202 ppm 102 7 10 10 3 pH 4.6 1246 ppm 0.5 M NaOAc H O 21.00 X 745 ppm 0.5 0.5 0.50.5 0.5 0.5 0.5 q IO M N pH 4.6 4578 m CH N CH 3 3 0.5 M NaOAc Serum20.50 X 727 ppm 2 0.5 0.5 l 3 l 0.5

o (:11 l0-"M pH 4.6 4469 ppm H I CI 0.5 M NaOAc H O 17.0 X l0" 603 ppm0.5 0.5 0.5 0.5 l 0.5 0.5 N pH 4.6 5355 ppm N w 0.5 M NaOAc Serum 17.0 x111- 603 ppm 2 0.5 1 1 6 1 1 o CH pH 4.6 5355 ppm Table 4 ANTIBACTERIALACTIVITY OF 3-CHLORO-2,2-ISPIRO-l'-METHYL-4-PIPER1D1NYL]-4.4-DIMETHYL-l.3-OXAZOL1D1NE ConditionsConcentration Data Antibacterial Activity. Time (min.) Buffer/ PositiveCompound pH Diluent Com- CI 1 228 10536 10031 9027 6538 4617 6501 pound0.5 M NaI-I POJI O 20.75 x 10*M 736 ppm 1 0.5 1 1 1 0.5 1 N N pH 7.04525 ppm 01 ,.c11

O CH 0.5 M NaH PO Serum 19.88 X 10 M 705 ppm 5 7 8 10 10 5 7 3 I pH 7.04334ppm H I. Cl N 0.5 M NaI-I PO H O 19.75 10-"M 700 m 4 1 1 1 4 1 1 CH3 CH3 0.5 M NaH PO 19.13 x IO M 678 ppm 10 4 10 10 10 10 10 0 CH3 @osoc11 TABLE 5 TABLE 6-Continued STABILITY OF 3-CHLORO 2,2-[SPIRO-l'-METHYL-4'- PIPERIDINIUM]4,4-DIMETHYL-l,3-OXAZOLID1NE HYDRO- CHLORIDEIN THE NEAT STATE AT 40C "Weight of sample analyzed. "Volume of lO"Nsodium thiosulfate required to titrate the sample at time (T).Percentage of positive chlorine in the sample analyzed.

TABLE 6 STABILITY OF 3-CHLORO-2,2-[SPIRO- l '-METHYL-4'-PIPERIDINIUM]1,3-OXAZOLIDINE METHANESULFONATE IN THE NEAT STATE AT 40CTime (days) Wt. (mg) V (m1)" 7c Cl STABILITY OF3-CHLORO-2,2-[SPIRO-l'-METHYL-4'- PIPERIDINIUM] 1,3-OXAZOL1DINEMETHANESULFONATE IN THE NEAT STATE AT 40C Time (days) Wt. (mg) V-,(ml)"Cl "Weight of sample analyzed. Volume of IO N sodium thiosulfaterequired to titrate the sample at time (T). Percentage of positivechlorine in the sample analyzed.

ANTIBACTERIAL ACTIVITY STUDIES The procedure employed to determine theantibacterial activity of 3-chloro-2,2,4,4-tetramethy1-1,3- oxazolidineand 3-ch1oro-2,2-[spiro-1'-methy1-4-piperidinyl]-4,4-dimethy1-l,3-oxazo1idine was basedprimarily on a modification of the serial dilution method of analysis.However, instead of determining the minimum inhibitory concentrationparameters for the compound investigated, applicants alternatively choseto determine the bactericidal endpoint for a given concentration of thecompound investigated. Consequently, applicants studies were establishedto determine the time required for complete sterilization of themicro-organism tested, when exposed to a given concentration of thecompound investigated.

The method and reagents employed in applicants antibacterial studies aredescribed below:

Overnight Organism ATCC Code Broth Culture (Organisms/m1) Slap/1.epidermidis 12228 5 X l0 E. ((111 10536 10 X 10 Kleb. pneumoniae 1003112 X 10- 13 X 10 Pseud. aeruginosa 9027 12 X 10- 13 10 Slap/1. aureus6538 6 X 10 8 X 10 Bord. bronchiseplica 4617 3 X '10 Nutrient BrothB.B.L. 8 g/lOOO ml distilled water. The broth contains 5 g gelysatepeptone and 3 g beef extract. The solution has a pH of 6.9. NutrientAgar 23 g/lOOO ml. distilled .water. The nutrient contains g gelysatepeptone, 3 g beef extract and 15 g agar.

Horse Serum T.C. horseserum solution in distilled water. The serumsolution was freshly prepared and adjusted to a pH of 7 using carbondioxide prior to its use.

METHOD A stock solution of each compound identified above was preparedusing an appropriate buffered solution.

For screening in the absence of a denaturing agent (e.g., horse serum)an equal volume of distilled water and the resulting solution wassubjected to the screen.

For screening in the presenceof a denaturing agent, a volume of thestock solution was diluted using an equal volume of 10% horse serum.When necessary, the final solution was adjusted to the desired pH using[N HCl and the solution was permitted to stand at room temperature for30 minutes prior to the screening procedure.

To 5 ml of the stock solution being evaluated, there was added 0.2 ml ofan overnight broth culture containing the particular micro-organismbeing investigated [see above). At time intervals of 0.5, l, 2, 3, 4, 5,minutes. a loop of this suspension was subcultured into 5 ml of asterile nutrient broth. All the samples were then incubated at 37C for 7days with daily observation for evidence of bacterial growth. The timeinterval reported is for that sample in which no bacterial growth wasobserved after the incubation period.

Aside from the foregoing, several controls were also employed asdescribed below.

CONTROL 1 This control was designed basically to insure viability of theovernight broth culture.

To 5 ml of a sterile 0.9% sodium chloride solution,

there was added 0.2 ml of an overnight broth culturecontaining theparticular micro-organism being investigated. A loop of this suspensionwas subcultured into 5 ml of a sterile nutrient broth and incubated at37C for 7 days.

CONTROL 2 This control was designed to insure that the dilution factorof the nutrient broth was beyond any bacteriostatic activity of eachcompound (as identified above) tested.

To 5 ml of a sterile nutrient broth there was added a loop of a solutionof each compound as described above and the solution was mixedimmediately. To this solution, there was then added a loop of anovernight broth culture which was diluted 25x with a 0.9% sodiumchloride solution. Incubation was carried out for 7 days at atemperature of 37C.

CONTROL 3 This control was employed to insure the bacterial growthobserved was that due to the organism being tested, rather thancontamination from a foreign organism.

At the same time intervals used for subculturing the test solution intonutrient broth during the screening procedure, a loop of the testsolution was also subcultured onto sterile nutrient agar plates. Thistechnique was useful for observing the characteristic colonialmorphology of each organism.

CONTROL 4 This control wasused 'initially'to insure that the pH of thesolution and the concentration of the buffer species did not inhibit thebacterial growth during the time intervals used in the screeningprocedure.

The entire screening procedure was conducted for each buffered solutionusing the buffered solution rather thanthe solution of each testedcompound in the procedure. 1 Y

By following the reaction scheme as illustrated in Examples I and II,all the compounds of the present invention can be'prepared. 1 I

While all compounds encompassed within applicants generic formula domeet applicants criteria, i.e., exhibit sufficient antibacterial andantifungal activity with low chlorine potential and remainnon-persistant, still, certain compounds are preferred. These compoundsare:

l 3-chloro-2,2,4,4-tetramethyl-1,3-oxazolidine 2.3-chloro-2,2,4,4-tetramethyl tetrahydro-l,3-

oxazine,

3. 3-chloro-2-methyl-2-(l-diethylamino-3-propyl)-4,4-dimethyl-1,3-oxazolidine or its HX salt,

'4. 3-chloro-2-methyl-2-(l-diethylamino-3-propyl)- 4,4-dimethyltetrahydro-l,3-oxazine or its l-IX salt,

5. 3-chloro-2,2[spirol -methyl-4'-piperidinyl]-4,4-

dimethyl-l,3-oxazolidine or its HX salt,

6. 3-chloro-2-methyl-2-(diethylaminoethyl)-4,4-

dimethyl-l,3-oxazolidine or its l-lX salts,

7. 3-chloro-2-methyl-2-(diethylaminomethyl)-4,4-

dimethyl-l,3-oxazolidine or its HX salts These compounds areconveniently used in aqueous solution. They may be applied by anyconventional means, e.g., spray, wipe, etc.

Although the present invention has been adequately described in theforegoing specification and examples included therein, it is obviouslyapparent that various changes and/or modifications can be made theretowithout departing from the spirit and scope thereof.

What we claim is:

1. A 3-Chloro-tetrahydro-l ,3-oxazine or oxazolidine compound of theformula:

(CR R Z j 4 Cl wherein each of R and R which may be the same ordifferent, represents an alkyl group of from I to 20 carbon atoms;wherein each of R and R which may be the same or different, represents ahydrogen atom or an alkyl group of from 1 to 20 carbon atoms; wherein 1represents an integer of l or 2; and wherein each of R and R.,, whichmay be the same or different, represents an alkyl group of from 1 to 20carbon atoms, a -(CH ),,X group, wherein n represents an integer of from1 to 20 and wherein X represents a member selected from the groupconsisting of a dimethylamino group, a diethylamino group, atrimethylammonium group, a triethylammonium group, a dimethylam- 1 1 12monium group, a diethylammonium group, a -COOR 6. The compound of claim1: group, a -OOCR group, and a OR,, group, wherein3-chloro-2-methyl-2-(diethylaminoethyl)-4,4- each of R through Rrespectively, represents a memdimethyl-l,3-oxazolidine or its HX salt,wherein X ber selected from the group consisting of an alkyl grouprepresents a pharmaceutically acceptable anion. of from 1 to carbonatoms or a benzyl group. 5 7. The compound of claim 1:

2. The compound of claim 1:3-chloro-2-methyl-2-(diethylaminomethyl))-4,4-3-chloro-2,2,4,4-tetramethyl-l ,3-oxazolidine. dimethyl-l ,3-oxazolidineor its HX salt, wherein X 3. The compound of claim 1: represents apharmaceutically acceptable anion.3-chloro-2,2,4,4-tetramethyl-tetrahydro-l ,3-oxazine. 8. The compound ofclaim 1 wherein R, and R rep- 4. The compound of claim 1: 10 resent analkyl group of from 1 to 5 carbon atoms. 3-chloro-2-methyl-2(l-diethylamino-3-propyl)-4,4- 9. The compound of claim 1, wherein R andR repdimethyl -1,3-oxazolidine or its HX salt, wherein X resent an alkylgroup of from 1 to 5 carbon atoms. represents a pharmaceuticallyacceptable anion. 10. The compound of claim 1, wherein R and R rep- 5.The compound of claim 1: 3-chloro-2-methyl-2- resent a hydrogen atom.l-diethylamino-3-propyl)-4,4-dimethyl-tetrahydro- 11. The compound ofclaim 1, wherein R and R repl,3-oxazine or its HX salt, wherein Xrepresents a pharresent an alkyl group of from 1 to 5 carbon atoms.

maceutically acceptable anion.

1. A 3-CHLORO-TETRAHYDRO-1,3-OAZINE OR OXAZOLIDINE COMPOUNDS OF THEFORMULA:
 2. The compound of claim 1:3-chloro-2,2,4,4-tetramethyl-1,3-oxazolidine.
 3. The compound of claim1: 3-chloro-2,2,4,4-tetramethyl-tetrahydro-1,3-oxazine.
 4. The compoundof claim 1: 3-chloro-2-methyl-2(1-diethylamino-3-propyl)-4,4-dimethyl-1,3-oxazolidine or its HX salt, wherein X represents a pharmaceuticallyacceptable anion.
 5. The compound of claim 1:3-chloro-2-methyl-2-(1-diethylamino-3-propyl)-4,4-dimethyl-tetrahydro-1,3-oxazine or its HX salt, wherein X represents a pharmaceuticallyacceptable anion.
 6. The compound of claim 1:3-chloro-2-methyl-2-(diethylaminoethyl)-4,4-dimethyl-1,3-oxazolidine orits HX salt, wherein X represents a pharmaceutically acceptable anion.7. The compound of claim 1:3-chloro-2-methyl-2-(diethylaminomethyl))-4,4-dimethyl-1,3-oxazolidineor its HX salt, wherein X represents a pharmaceutically acceptableanion.
 8. The compound of claim 1 wherein R1 and R2 represent an alkylgroup of from 1 to 5 carbon atoms.
 9. The compound of claim 1, whereinR5 and R6 represent an alkyl group of from 1 to 5 carbon atoms.
 10. Thecompound of claim 1, wherein R5 and R6 represent a hydrogen atom. 11.The compound of claim 1, wherein R3 and R4 represent an alkyl group offrom 1 to 5 carbon atoms.